The epidermal growth factor receptor (EGFR) is upregulated in squamous cell carcinomas of the head and neck (SCCHN) where EGFR expression levels in the tumor correlate with decreased survival. The EGFR monoclonal antibody, cetuximab, was FDA-approved in 2006 for the treatment of SCCHN and is the first new drug for this cancer in 45 years. However, despite the ubiquitous expression of EGFR in SCCHN tumors, the clinical response rate to cetuximab as single agent therapy is limited, underscoring the importance of elucidating the mechanisms of persistent tumor growth in the setting of EGFR blockade. We have accumulated extensive evidence that EGFR-mediated activation of selected Signal Transducers and Activators of Transcription (STATs) and Src family kinases contribute to SCCHN growth and survival. We recently reported that a mutant EGFR, EGFRvIII is expressed in up to 40% of SCCHN where EGFRvIII is associated with therapeutic resistance, including resistance to cetuximab. Therefore, we propose to test the overall hypothesis that the loss of growth control in SCCHN is mediated by aberrant EGFR signaling though both mutant and wild-type receptors involving selective activation of STAT proteins and/or Src kinases, with the ultimate aim of designing novel treatment strategies to target these pathways. To accomplish the goals of this proposal, we will: 1) determine the role of Src kinases in EGFR-mediated and EGFR-independent growth pathways in SCCHN;2) elucidate the contribution of STAT5 activation to SCCHN progression and response to EGFR blockade;and 3) determine the role of STAT and Src signaling in mediating the oncogenic properties of EGFRvIII in SCCHN. PUBLIC HEALTH RELEVANCE: The proposed studies will elucidate the mechanisms of resistance to EGFR targeting strategies in preclinical models of squamous cell carcinoma of the head and neck. In addition, we will test the hypothesis that STATs, Src family kinases and EGFRvIII contribute to cetuximab resistance in 2 SCCHN patient cohorts.